By Philip Trum
When older people talk about resting their weary bones, they’re not waxing metaphoric: Decades of movement and support takes a natural toll on our bones — a toll that becomes even more pronounced when pathologies come into play. Based at McGill, and bringing together researchers from across Quebec, the Centre for Bone and Periodontal Research is searching for better ways to treat two diseases that make our aging bones even more weary (and painful): osteoporosis and osteoarthritis.
In Shakespeare’s The Tempest, Prospero venomously vows to “Fill all thy bones with aches, make thee roar / That beasts shall tremble at thy din.” The threat sends his insolent servant scurrying, and rightly so: As millions of Canadians in their sixties and seventies will readily attest, bone pain can be excruciating.
Osteoporosis is a disease characterized by a progressive loss of bone strength. It usually makes itself known around age 60 to 65, but may begin even earlier; about 70 per cent of osteoporosis patients are women. If left unchecked, the disease can decimate bones to the point that they are extremely susceptible to fractures. In his research, Dr. David Goltzman has helped uncover some surprises about osteoporosis.
Goltzman is director of the Calcium Research Laboratory of the MUHC, and a professor of medicine and physiology in the Faculty of Medicine. Among his studies in osteoporosis, he is exploring the relationship between osteoporosis and cardiovascular disease, two ailments that are common in the plus-65 set. He suspects that the same mechanisms that put calcium into bone (a good thing) also conspire to calcify blood vessels (a bad thing). This means, unfortunately, that standard osteoporosis treatment (bone-boosting dosages of calcium and vitamin D) may put people at higher risk for vascular calcification. Translation: Curb your osteoporosis and you open the door to heart disease and stroke. “It may be that what is good for one isn’t good for the other,” Goltzman says, “but there may be an optimal level of osteoporosis treatment that doesn’t put you at increased risk for cardiovascular disease.” Determining how calcium and hormones such as vitamin D work, and what the optimal levels are for their effectiveness, is currently a major preoccupation of his research team and should help in the understanding and treatment of both diseases.
That isn’t the only recent change to how we think about — and, therefore, treat — osteoporosis. As the director of the Centre for Bone and Periodontal Research — a collaboration between McGill’s faculties of Dentistry and Medicine that brings together basic scientists and clinical investigators from several Quebec universities — Goltzman heads the Canadian Multicentre Osteoporosis Study (CaMos). The prospective cohort study has been following some 10,000 individuals, from nine cities, for almost 14 years. (It’s the largest ever Canadian osteoporosis study.) CaMos has generated a wealth of data that is helping to better diagnose the disease. In fact, the study has suggested that bone mineral density, as an indicator, may not be all it’s been cracked up to be. “Bone mineral density (BMD) used to be the sine qua non for diagnosing osteoporosis,” Goltzman says. “If BMD was low, you treat. But, as we analyzed all this detailed CaMos data, we started to find that most of the osteoporotic fractures occurred in people who did not have very low bone density. Low bone density isn’t inconsequential, but it doesn’t have the same implications for a 40-year-old that it has for a 60-year-old.”
Osteoporosis affects one in four Canadian women over the age of 50.
Although osteoporosis therapies are becoming increasingly effective at halting the disease, preventing from 30 to 70 per cent of fractures, osteoarthritis cannot be slowed or cured. Osteoarthritis is caused by the thinning of the shock-absorbing cartilage covering the ends of bones. Physicians have little recourse but to treat pain — or, as a last resort, to surgically replace problematic joints. “It’s really an area that’s ripe for new drug discoveries and therapies,” says Goltzman.
That’s exactly what Dr. John Di Battista and his colleagues at the Royal Victoria Hospital are working toward. Di Battista is a professor of medicine in the Faculty of Medicine. There are currently no reliable biomarkers for early detection of osteoarthritis, and no therapies for reversing or even slowing the disease’s progression. (There are, however, drugs for modifying the progression of rheumatoid arthritis.) You therefore don’t know you have the disease until you have symptoms, at which time it may be too late to do anything other than try to reduce pain, swelling and inflammation. “Basically, our treatments are rather primitive,” says Di Battista.
Osteoarthritis usually affects weight-bearing joints, such as knees, ankles and hips. It usually strikes people in their sixties and seventies, and women are three to four times more prone than men (at least in terms of patients requiring remedial surgery). Because the disease can’t be reversed, late-stage osteoarthritis sufferers are often left with no choice but to undergo joint replacement surgery; in Montreal alone, more than two thousand osteoarthritis-related hip and knee arthroplasties are performed each year.
Di Battista receives three or four surgical specimens from orthopedic surgeons every week (mostly from knee and hip replacements). One of the things Di Battista looks at in each sample is the synovial membrane, which normally envelops the joint and contains joint-lubricating synovial fluid.
For something so important, a healthy synovial membrane is only one or two cells thick, and is modestly vascularized. In his surgical samples, though, Di Battista has been seeing a lot of inflamed membranes that are unnatural in both thickness and excessive blood vessel count. Increased vascularization acts as a gateway for immune cells to infiltrate the membrane. The problem with immune cells sneaking into places they shouldn’t be? They signal the body to attack itself. In this case the victim is cartilage. After years of study, Battista has identified some of the mechanisms that activate this kind of inflammation-based osteoarthritis. He’s now working to develop therapeutic interventions that would interrupt the process by blocking intermediary molecules.
“Right now, this type of osteoarthritis is the only case where we think we can modify the disease,” he says. “From what we currently know, we can’t stop osteoarthritis that’s caused by injury, overuse or genetics — but 20 to 30 per cent of osteoarthritis cases are caused by inflammation, so it’s still very important.”
Di Battista’s lab is also studying some possible genetic causes of osteoarthritis. “You’d think that a progressive disease that mainly strikes people later in their sixth or seventh decade of life wouldn’t have a genetic component,” he says, “but there are a few genes we’re currently investigating that may predispose individuals to osteoarthritis.” One such group is people who have hemochromatosis, a blood disease that causes iron overload. These people often develop osteoarthritis in their forties — some 20 years earlier than most osteoarthritis sufferers. What’s more, their form of osteoarthritis, unlike “traditional” osteoarthritis, manifests itself symmetrically: Instead of just affecting one hip, for example, it affects both at the same time. Approximately one in 400 people have the genetic mutation that puts them at risk for hemochromatosis-influenced osteoarthritis.
“Right now, we can only treat the symptoms of people with established or even advanced disease,” Di Battista says. “Our goal is, through the identification of biomarkers, to start preventative therapies before patients experience debilitating pain or loss of mobility, ensuring a better quality of life well into the seventh or eighth decade.”
The CIHR recently renewed funding for the Canadian Multicentre Osteoporosis Study for five years. The study also receives support from Amgen, Lilly, Merck and Novartis-DG. Dr. Di Battista’s work has been supported for some 20 years by funds from the CIHR and the Arthritis Society of Canada.